Cancer Treatment Today

Osimertinib, also known as AZD9291, is a novel EGFR TKI developed by AstraZeneca, the structure and pharmacology of which are distinct from other third-generation EGFR TKIs.14 It shows 200-fold selectivity for T790M/L858R protein over wild-type EGFR and has been classed as a “breakthrough” compound for fast-track development, having demonstrated perfect objective response rate (ORR) in patients with T790M-positive NSCLC who had progressed on a first-generation EGFR TKI. Osimertinib received its first global approval by the US Food and Drug Administration in November 2015 for patients with metastatic EGFR T790M-positive NSCLC who had progressed on prior systemic therapy, including an EGFR TKI.

The specific types of activating mutations that confer sensitivity to EGFR TKIs are present in the tyrosine kinase (TK) domain of the EGFR gene. Exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21 are the most frequent in NSCLC and are termed ‘classical’ mutations.

Tagrisso is specifically indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer, as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy. However, recent studies (Soria et al) suggest that it also works without such a mutation and NCCN lists it first line now.There is evidence supporting its effectiveness also for brain metastases.Yang performed eh BLOOM study, which concluded: “Encouraging activity and manageable tolerability in pts with LM from EGFRm NSCLC was observed at 160 mg qd, with a median treatment duration of 6.0 m; continued evaluation is ongoing.”.
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Vansteenkiste J, et al. CNS Response to Osimertinib Vs. Standard-of-Care EGFR-TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC: FLAURA. Presented at ESMO Asia 2017 Congress; November 17-19, 2017; Singapore. Abstract LBA5.

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at: 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract LBA2_PR.

JC Soria et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer N Engl J Med 378 (2), 113-125. 2017 Nov 18.

Haijun Zhang, Osimertinib making a breakthrough in lung cancer targeted therapy. Onco Targets Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, Onc Ther. 2016; 9: 54895493.

Tagrisso, Prescribing Information 2019

NCCN, NSC Lung, NSCL-I 2018

Geoffrey R. Oxnard et al, Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer. Journal of Clinical Oncology 34, no. 28 (October 2016) 3375-3382.